scholarly journals Biallelic loss of FAM46C triggers tumor growth with concomitant activation of Akt signaling in multiple myeloma cells

2020 ◽  
Vol 111 (5) ◽  
pp. 1663-1675 ◽  
Author(s):  
Jo Kanasugi ◽  
Ichiro Hanamura ◽  
Akinobu Ota ◽  
Sivasundaram Karnan ◽  
Vu Quang Lam ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Tumor Growth ◽  
Akt Signaling ◽  
Myeloma Cells

Autocrine Sonic Hedgehog Protects Multiple Myeloma Cells From Apoptosis and Enhances Drug Resistance

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2904-2904
Author(s):  
Zhiqiang Liu ◽  
Yuhuan Zheng ◽  
Haiyan Li ◽  
Yong Lu ◽  
Donna M. Weber ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Tumor Growth ◽  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Conflicts Of Interest ◽  
Myeloma Cells ◽  
Apoptosis Rate ◽  
Chemotherapy Drugs

Abstract Abstract 2904 The secreted protein sonic hedgehog (SHH) and the hedgehog signaling are of great importance in proliferation and differentiation of cells in the hematopoietic system, and also play a vital role in oncogenesis of B cell malignance. However, the functions and mechanism of SHH signaling in multiple myeloma (MM) is mostly unknown. Thus far, aberrant activation of the hedgehog signaling in tumor growth promoting and/or survival capabilities as well as a paracrine model of SHH secretion have been demonstrated in MM. In the current study, we demonstrated a new autocrine SHH functioning manner in MM cells. The Shh mRNA and the SHH protein were highly expressed both in the MM cell lines and in purified CD138+ MM cells from patients using real-time PCR, Western Blot and immunohistochemistry analyses, respectively; and the SHH protein was also detected in the culture medium. Accordingly, the Hh ligand receptor PTCH1 and PTCH2 as well as the transcriptional factor GLI1 were all overexpressed in MM cells, indicating the activation of Hh signaling pathway. Autocrine SHH played a role in MM cells survival and protected MM cells from apoptosis in vitro, and autocrine SHH accelerated xenograft tumor growth in myeloma-SCID mouse model in vivo. Moreover, autocrine SHH enhanced drug resistance of MM cells, as SHH overexpressed CAG cells (SHH+CAG) had a significantly low apoptosis rate when treated with chemotherapy drugs dexamethasone or bortezomib, as compared with wild type cells (wt-CAG). On the contrary, SHH knockdown cells (SHH-CAG) had a dramatically higher apoptosis rate. Blocking autocrine SHH ligand and treating cells with dexamethasone or bortezomib significantly improved the drug killing effect. Finally, we found that upregulated BLC2 via SHH-Gli1signaling is the signaling pathway by which MM cells enhanced the drug resistance. Our study provides a new insight into the biologic function of the autocrine SHH in proliferation, survival and the drug resistance in the myeloma cells. Disclosures: No relevant conflicts of interest to declare.

Suppression of tumor growth by a heterologous antibody directed against multiple myeloma dominant CD38 antigen in SCID mice injected with multiple myeloma cells

2017 ◽  
Vol 24 (3-4) ◽  
pp. 53-57 ◽  
Author(s):  
Arpad Z. Barabas ◽  
Chad D. Cole ◽  
Richard M. Graeff ◽  
Zoltan B. Kovacs ◽  
Rene Lafreniere
Keyword(s):  
Multiple Myeloma ◽  
Tumor Growth ◽  
Scid Mice ◽  
Myeloma Cells ◽  
Cd38 Antigen ◽  
Heterologous Antibody

scholarly journals Targeting CD47/TNFAIP8 by miR-155 overcomes drug resistance and inhibits tumor growth through induction of phagocytosis and apoptosis in multiple myeloma

Haematologica ◽  
2019 ◽  
Vol 105 (12) ◽  
pp. 2813-2823 ◽  
Author(s):  
Nasrin Rastgoo ◽  
Jian Wu ◽  
Mariah Liu ◽  
Maryam Pourabdollah ◽  
Eshetu G. Atenafu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Tumor Growth ◽  
Myeloma Cell ◽  
Therapeutic Modality ◽  
Drug Resistant ◽  
Myeloma Cells ◽  
Advanced Stages

The mechanisms of drug resistance in multiple myeloma are poorly understood. Here we show that CD47, an integrin-associated receptor, is significantly upregulated in drug resistant myeloma cells in comparison with parental cells, and that high expression of CD47 detected by immunohistochemistry is associated with shorter progression free and overall survivals in multiple myeloma patients. We show that miR-155 is expressed at low levels in drug resistant myeloma cells and is a direct regulator of CD47 through its 3'UTR. Furthermore, low miR-155 levels are associated with advanced stages of disease. MiR-155 overexpression suppressed CD47 expression on myeloma cell surface, leading to induction of phagocytosis of myeloma cells by macrophages and inhibition of tumor growth. MiR-155 overexpression also re-sensitized drug-resistant myeloma cells to bortezomib leading to cell death through targeting TNFAIP8, a negative mediator of apoptosis in vitro and in vivo. Thus, miR-155 mimics may serve as a promising new therapeutic modality by promoting phagocytosis and inducing apoptosis in patients with refractory/relapsed multiple myeloma.

scholarly journals Activation of NF-κB and upregulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications

Oncogene ◽  
2002 ◽  
Vol 21 (37) ◽  
pp. 5673-5683 ◽  
Author(s):  
Constantine S Mitsiades ◽  
Nicholas Mitsiades ◽  
Vassiliki Poulaki ◽  
Robert Schlossman ◽  
Masaharu Akiyama ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Akt Signaling ◽  
Myeloma Cells ◽  
Therapeutic Implications ◽  
Human Multiple Myeloma ◽  
Apoptotic Proteins

scholarly journals CSF1R-Inhibition and Reduction of Macrophages Delays Multiple Myeloma Growth in a Non-T-Cell-Dependent Manner

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5717-5717
Author(s):  
Fredrik H. Schjesvold ◽  
Ole Audun Haabeth ◽  
Bjarne Bogen ◽  
Anders Tveita
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Dependent Manner ◽  
Colony Stimulating Factor ◽  
M1 Macrophages ◽  
Myeloma Cells ◽  
Tumor Killing ◽  
Stimulating Factor

Abstract Macrophages are important tumor-promoting cells, and can constitute up to half of the tumor mass, orchestrating remodeling, inducing angiogenesis and suppressing the immune system to terminate local inflammatory responses. Colony stimulating factor (CSF-1), also known as macrophage colony-stimulating factor (M-CSF), is the most important cytokine involved in survival, proliferation and differentiation of tissue macrophages and their precursors. Previous experiments from our group has shown that amount of CSF-1 in the tumor bed correlates with successful rejection of cancer cells in a TCR-transgenic model where CD4+ T cells recognize a tumor specific antigen produced by multiple myeloma cells. We therefore tested if reduced signaling via CSF-1R, and thereby a decrease in tumor infiltrating macrophages, would results in decreased growth of multiple myeloma cells. . PLX3397, a tyrosine kinase inhibitor with specificity for CSF1R and KIT, has been demonstrated to delay tumor growth in a CD8+ T-cell-dependent manner after chemotherapeutic treatment in a murine model of mammary carcinogenesis. Here, we show that MOPC315 multiple myeloma cells implanted subcutaneously in matrigel plugs in SCID mice become infiltrated with M2 phenotype macrophages that enhances their growth. When given chow containing PLX3397, recruitment of macrophages is strikingly reduced, with significant delay in tumor growth. Importantly, this delay in tumor development is not T cell dependent, since the anti-tumor effect is seen in T cell deficient SCID-mice as well as in BALB/c mice. Importantly, treatment with PLX3397 does not abrogate efficient tumor killing, and does not affect survival, when tested in a TCR-transgenic model where CD4+ T cells via induction of M1 macrophages reject multiple myeloma. In conclusion, PLX3397 delays tumor growth by reducing amounts of tumor infiltrating M2 macrophages, while rendering effective tumor killing by M1 macrophages uninhibited. Thus, drugs that inhibit signaling of CSF-1 could be of value in treatment of multiple myeloma. Disclosures No relevant conflicts of interest to declare.

scholarly journals Bone morphogenetic protein 4 gene therapy in mice inhibits myeloma tumor growth, but has a negative impact on bone

2019 ◽  
Author(s):  
Marita Westhrin ◽  
Toril Holien ◽  
Muhammad Zahoor ◽  
Siv Helen Moen ◽  
Glenn Buene ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Multiple Myeloma ◽  
Bone Formation ◽  
Tumor Growth ◽  
Trabecular Bone ◽  
Bone Morphogenetic Protein ◽  
Bone Morphogenetic Protein 4 ◽  
Myeloma Cells ◽  
Morphogenetic Protein ◽  
Virus Serotype

AbstractMultiple myeloma is characterized by accumulation of malignant plasma cells in the bone marrow. Most patients suffer from an osteolytic bone disease, caused by increased bone degradation and reduced bone formation. Bone morphogenetic protein 4 (BMP4) is important for both pre- and postnatal bone formation and induces growth arrest and apoptosis of myeloma cells. BMP4-treatment of myeloma patients could have the potential to reduce tumor growth and restore bone formation. We therefore explored BMP4 gene therapy in a human-mouse model of multiple myeloma where humanized bone scaffolds were implanted subcutaneously in RAG2−/−γC−/−mice. Mice were treated with adeno-associated virus serotype 8 BMP4 vectors (AAV8-BMP4) to express BMP4 in the liver. When mature BMP4 was detectable in the circulation, myeloma cells were injected into the scaffolds and tumor growth was examined by weekly imaging. Strikingly, the tumor burden was reduced in AAV8-BMP4 mice compared with the AAV8-CTRL mice, suggesting that increased circulating BMP4 reduced tumor growth. BMP4-treatment also prevented bone loss in the scaffolds, most likely due to reduced tumor load. To delineate the effects of BMP4 overexpression on bone per se, without direct influence from cancer cells, we examined the unaffected, non-myeloma femurs by μCT. Surprisingly, the AAV8-BMP4 mice had significantly reduced trabecular bone volume, trabecular numbers, as well as significantly increased trabecular separation compared with the AAV8-CTRL mice. There was no difference in cortical bone parameters between the two groups. Taken together, BMP4 gene therapy inhibited myeloma tumor growth, but also reduced the amount of trabecular bone in mice. Our data suggest that care should be taken when considering using BMP4 as a therapeutic agent.

Bortezomib-Induced Reversal of CAM-DR Phenotype in Myeloma Is Associated with AKT and ERK1/2 Signaling.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3357-3357
Author(s):  
Ramadevi Nimmanapalli ◽  
Lori Hazlehurst ◽  
Steven Enkemann ◽  
Melissa Alsina ◽  
William S. Dalton
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Tumor Cell ◽  
Expression Profiles ◽  
Specific Inhibitor ◽  
Gene Expression Profiles ◽  
Akt Signaling ◽  
Chemotherapeutic Agents ◽  
Dependent Manner ◽  
Myeloma Cells

Abstract An increasing body of evidence suggests that interactions between myeloma cells and the microenvironment are critical for tumor cell survival, proliferation and drug resistance. These pro-survival interactions include binding of soluble factors, and direct contact with stromal cells, or extra cellular matrix (ECM) components such as fibronectin (FN). More specifically, adhesion of multiple myeloma (MM) to FN via ν1 integrins has been demonstrated to confer resistance to a host of chemotherapeutic agents (Shain et al., 2000). This anti-apoptotic phenomenon, termed cell adhesion-mediated drug resistance (CAM-DR), is an intrinsic pathway for evading the therapy-induced apoptosis (Damiano et al., 2000). Bortezomib (PS-341), a specific inhibitor of proteosome, has been shown to cause apoptosis of several tumor cell lines including multiple myeloma. In contrast to conventional cytotoxics, Bortezomib, showed more apoptosis in 24 hours for 8226 myeloma cells adhered to FN (25 % 10 nM) compared to cells in suspension (10 % 10 nM) in a dose -dependent manner. To investigate the signal transduction mechanism responsible for the reversal of CAM-DR phenotype by Bortezomib, we conducted Affymetrix GeneChipÒ Expression of 8226 cells cultured either in suspension, or adhered to FN in the presence and absence of Bortezomib (50 nM) for 4 and 24 hours using the Affymetrix U133A chips. A total of 197 genes were upregulated on FN compared to suspension, among which only 12 genes were increased with Bortezomib and 105 genes were decreased with PS-341. A total of 870 genes were downregulated on FN adhesion, among which the majority of them were increased with Bortezomib. Similar patterns of gene expression profiles were observed after 24 hrs of treatment with Bortezomib. To examine how Bortezomib is reversing CAMDR phenotype, we chose to examine the genes that were changed with FN adhesion and reversed when treated with Bortezomib. The adhesion of 8226 cells to FN enhanced both ERK1/2 and AKT signaling pathways, and both pathways were down regulated when treated with Bortezomib. The main indicators of the AKT signaling on FN are upregulation of PYK2, AKT2, MDM2 and downregulation of p21 and BAD. In conformation with our micro-array data, PYK2 phosphorylation and ERK1/2 phosphorylation were enhanced when 8226 cells were adhered to FN. The mechanisms to understand role of PYK2 phosphorylation and downstream AKT signaling in Bortezomib-induced reversal of CAMDR are under investigation.

A Novel Orally Active Small Molecule Potently Induces G1 Arrest in Primary Myeloma Cells and Prevents Tumor Growth by Specific Inhibition of Cdk4/6.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 369-369 ◽  
Author(s):  
Linda B. Baughn ◽  
Maurizio Di Liberto ◽  
Kaida Wu ◽  
Peter Toogood ◽  
Tracey Louie ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Tumor Growth ◽  
Small Molecule ◽  
Critical Role ◽  
Cellular Transformation ◽  
G1 Arrest ◽  
Specific Inhibition ◽  
Myeloma Cells ◽  
Orally Active

Abstract Cell cycle deregulation is central to the initiation and fatality of multiple myeloma, the second most common hematopoietic cancer, although impaired apoptosis plays a critical role in the accumulation of myeloma cells in the bone marrow (BM). Inhibition of Cdk4 and Cdk6 by the Cdk inhibitor, p18(INK4c), is required for the generation of normal, functional plasma cells1. The mechanism for intermittent, unrestrained proliferation of myeloma cells is unknown, but mutually exclusive activation of Cdk4-cyclin D1 or Cdk6-cyclin D2 precedes proliferation of BM myeloma cells in vivo2. These data identify Cdk4 and Cdk6 as key determinants in the loss of cell cycle control in myeloma and suggest that Cdk4/6 may be effective targets for therapeutic intervention. Here we show that by specific inhibition of Cdk4/6, the orally active small molecule PD 0332991 potently induces G1 arrest in primary BM myeloma cells ex vivo, and prevents tumor growth in disseminated human myeloma xenografts. PD 0332991 inhibits Cdk4/6 proportional to the cycling status of the cells independent of cellular transformation, and acts in concert with the physiologic Cdk4/6 inhibitor p18(INK4c). Inhibition of Cdk4/6 by PD 0332991 is not accompanied by induction of apoptosis. However, when used in combination with a second agent such as dexamethasone, PD 0332991 markedly enhances the killing of myeloma cells by dexamethasone. PD 0332991, therefore, represents the first promising and specific inhibitor for therapeutic targeting of Cdk4/6 in multiple myeloma and possibly other B cell cancers.

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